Immunosuppressed individuals have an increased risk of developing ultraviolet-radiation (UV)-induced non-melanoma skin cancer. Transplant recipients have the highest risk, 100-250 times that of the general population, and tend to develop multiple, aggressive squamous cell carcinomas (SCC). The immunobiology of post-transplant skin cancer, including the influence of immunosuppresslon on skin cancer development, has not been systematically investigated, and few clinical trials have been undertaken to prevent skin cancer in transplant patients. An appropriate animal model would greatly enhance studies aimed at 1) determining the mechanism by which immunosuppressive therapy enhances the risk of SCC, 2) testing the feasibility of chemoprevention strategies for reducing susceptibility to SCC in transplant patients, and 3) comparing the efficacy of different chemotherapeutic approaches in this population. CD4-leukopenia is considered a risk factor for skin cancer in transplant patients, and at least 23% of transplant patients have significantly reduced numbers of circulating CD4+ T cells. Our preliminary data demonstrate that depletion of CD4+ cells enhances UVB-induced inflammation and the development of skin tumors in hairless mice (Figures 3, 5-7). These observations provide us with two early markers of increased skin tumor susceptibility: cutaneous inflammation and systemic CD4+ T cell depletion. This application defines and develops an animal model appropriate for chemoprevention studies in post-transplant skin cancer, by characterizing the early inflammatory changes in skin that are predictive of increased skin tumor risk under conditions of immunosuppression (Specific Aim 1), and characterizing tumor multiplicity and tumor progression in hairless mice treated with clinically relevant immunosuppressants (Specific Aim 2). Our model will provide us with an experimental system suitable for studying underlying mechanisms of effective chemoprevention strategies in immunosuppressed individuals. Our team of investigators is uniquely able to develop and define this model due to complementary expertise in transplant and cellular immunology (VanBuskirk), photo-carcinogenesis (Oberyszyn, Kusewitt), chemoprevention (Oberyszyn) and mouse pathobiology (Kusewitt). This model will provide the pre-clinical basis for new clinical trials in immunosuppressed patients, who are at extremely high risk for developing life-threatening, UV-induced SCC.